Effects of tubulin-inhibiting agents in human lung and breast cancer cell lines with different multidrug resistance phenotypes.
Drug sensitivity was studied for the tubulin inhibitors taxol, taxotere, rhizoxin and for doxorubucin and cisplatin, in human lung and breast cancer cell lines, including drug-selected cell lines, overexpressing the membrane transporter P-glycoprotein (Pgp) or the multidrug resistance protein (MRP). All tubulin-inhibiting agents were more potent than doxorubicin and cisplatin in all cell lines. In the drug resistance-selected cell lines (doxorubicin or mitoxantrone resistant) there was cross-resistance between the tubulin inhibitors and the selecting agent; however, MRP overexpressing cells were relatively less resistant to taxanes than the Pgp overexpressing cells. Polymerization of microtubules after exposure to taxol was observed in drug sensitive cell lines, but not in resistant cell lines, even at high taxol concentrations and after long exposure times. In the Pgp overexpressing cell lines, steady accumulation of 14C-taxol was defective and could be reverted by verapamil. MRP overexpressing cells did not have a significant accumulation defect of taxol, compared to the parental cell lines, and verapamil did not have any effect. These data confirm that the Pgp overexpression is an important mechanism of resistance to taxanes and rhizoxin in human lung and breast tumor cells. However, the presence of mechanisms other than transport defects may play an important role in non-Pgp expressing cells, and these may include an altered function of tubulins.
van Ark-Otte
J
J
University Hospital Vrije Universiteit, Department of Oncology, Amsterdam, The Netherlands.
Samelis
G
G
Rubio
G
G
Lopez Saez
J B
JB
Pinedo
H M
HM
Giaccone
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D001943:Breast Neoplasms / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D000077143:Docetaxel; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007783:Lactones / Q000633:toxicity; D008175:Lung Neoplasms / Q000235:genetics; D018942:Macrolides; D008870:Microtubules / Q000187:drug effects / Q000473:pathology; D008942:Mitoxantrone / Q000633:toxicity; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000633:toxicity; D010641:Phenotype; D043823:Taxoids; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007783:Lactones; D018942:Macrolides; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel; D004317:Doxorubicin; D008942:Mitoxantrone; C041443:rhizoxin; D014700:Verapamil; D017239:Paclitaxel; D002945:Cisplatin